Prevention and Diagnosis

Clinical Presentation

The estimated incubation period for COVID-19 is up to 14 days from the time of exposure, with a median incubation period of 4 to 5 days. Patients with COVID-19 often have clinical manifestations of fever (85–89%), cough (68–86%), and shortness of breath (19–80%). In a study of 1,099 confirmed cases hospitalized with COVID-19, fever was present in 43.8% of patients at admission but ultimately developed in 88.7% of patients during hospitalization.1

Less common symptoms are nausea (24%), muscle ache (11–15%), confusion (9%), headache (8–14%), sore throat (5–18%), nasal congestion/rhinorrhea (5–16%), chest pain (2%), and diarrhea (2–27%). Other reported symptoms have included anosmia, dysgeusia, sputum production, dizziness, abdominal pain, anorexia, and vomiting. 1-3

Clinical Course

The clinical spectrum of COVID-19 ranges from asymptomatic to respiratory failure to multiorgan and systemic manifestations. A large study of 44,672 confirmed COVID-19 cases identified by the Chinese Centers for Disease Control and Prevention found that4:

  • 81% of cases were mild (e.g., non-pneumonia and mild pneumonia)
  • 14% of cases were severe (e.g., dyspnea, respiratory frequency ≥30/min, blood-oxygen saturation ≤93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300 mm Hg, and/or lung infiltrates >50% within 24 to 48 hours)
  • 5% of cases were critical (e.g., respiratory failure, septic shock, and/or multiple organ dysfunction or failure)

The overall case-fatality rate (CFR) identified in this study was 2.3%. No deaths were reported among mild and severe cases, but the CFR was 49.0% among critical cases.4

In Italy, up to 12% of all positive COVID-19 cases required admission to the intensive care unit (ICU).5 A study of hospitalized patients in China found that 32% were admitted to the ICU.6 The median time from symptom onset to the development of pneumonia is 5 days, and the median time from symptom onset to severe hypoxemia and ICU admission is 7–12 days. Acute hypoxemic respiratory failure from acute respiratory distress syndrome (ARDS) is the most common complication, found in 60–70% of patients admitted to the ICU. Shock (30%), myocardial dysfunction (20–30%), and acute kidney injury (10–30%) also account for a substantial number of complications related to COVID-19.5

Risk Factors for Severe Illness

In a study of 44,672 confirmed COVID-19 cases in China, the CFR was elevated among those with preexisting comorbid conditions, including cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6.0%), and cancer (5.6%).4 A study of 1482 patients hospitalized with COVID-19 in the United States (US) found that 89.3% had one or more underlying conditions, the most common being hypertension (49.7%), obesity (48.3%), chronic lung disease (34.6%), diabetes mellitus (28.3%), and cardiovascular disease (27.8%).

Age is another important factor impacting disease severity. Compared with the overall CFR of 2.3% in the study in China, the CFR was elevated in patients ≥80 years of age (14.8%) and in those aged 70–79 years (8.0%). A preliminary analysis of the mortality rate in the US between February 12 and March 16, 2020 found that the fatality of COVID-19 ranges from 10% to 27% in persons aged ≥85, followed by 3% to 11% in persons aged 65–84 years, 1% to 3% among persons aged 55–64 years, and <1% in persons aged 20–54 years.7

Laboratory Findings

A retrospective study of 150 patients in Wuhan, China identified several predictors of fatal outcome in COVID-19 cases, including older age, the presence of underlying diseases or secondary infections, and elevated inflammatory indicators in the blood. Laboratory results showed significant differences in white blood cell counts and platelets, cardiac troponin, myoglobin, C-reactive protein (CRP), and interleukin-6 (IL-6) between patients who recovered from COVID-19 and those who died from viral complications.8 A meta-analysis found the most frequent laboratory abnormalities with COVID-19 were lymphopenia (35–75% of cases) and increased CRP levels (75–93% of cases), lactate dehydrogenase (LDH) (27–92% of cases), erythrocyte sedimentation rate (ESR) (up to 85% of cases), and D-dimer (36–43% of cases), as well as low concentrations of serum albumin (50–98% of cases) and hemoglobin (41–50%). Laboratory abnormalities that were predictive of adverse outcome included lymphopenia, neutrophilia, and elevated levels of LDH, CRP, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).9

COVID-19 patients with ARDS showed abundant interstitial mononuclear inflammatory infiltrate in the lungs, particularly lymphocytes, implying that immune hyperactivation may be at least partially responsible for the severity of COVID-19 in these patients.10 These laboratory features, combined with the fever and confusion commonly found in critically ill patients infected with COVID-19, suggest the presence of a cytokine storm syndrome (CSS) that results in ARDS and multiorgan failure. 2,11,12 CSS is believed to be a consequence of an accentuated immune response to various triggers, including certain viral infections.

Radiographic Findings

In the early phase of pneumonia induced by COVID-19, the main computed tomography (CT) findings include multifocal peripheral and basal ground-glass opacities, crazy-paving patterns, traction bronchiectasis, and air bronchogram signs. A progressive transition to consolidation, together with pleural effusion, extensive small lung nodules, irregular interlobular or septal thickening, and adenopathies characterize the more advanced phase of the disease.13

In a recent report of 41 patients with COVID-19, abnormal chest imaging findings were observed in all patients, with 40 individuals having bilateral disease at initial imaging. ICU patients commonly exhibit bilateral subsegmental areas of air-space consolidation. Non-ICU patients typically show transient areas of subsegmental consolidation early, with bilateral ground-glass opacities predominating in later stages of the disease.6 Another study of 99 confirmed COVID-19 cases in a hospital in Wuhan, China found bilateral lung involvement in 75% of patients and unilateral pneumonia in 25% of cases. Multiple mottling and ground-glass opacity were found in 14% of cases. Additionally, pneumothorax occurred in one patient in this report.2 No pleural effusion or cavitation has been reported so far in confirmed cases of COVID-19-associated pneumonia. Overall, the imaging findings are highly nonspecific and may overlap with the symptoms of H1N1 influenza, cytomegalovirus pneumonia, or atypical pneumonia.14

Prevention

Infection Control – COVID-19 is extremely transmissible, with every case seeding more than two secondary cases. The WHO-China Joint Mission report found that healthcare workers accounted for 3.7% of cases with laboratory-confirmed COVID-19 in China.5 A large study of confirmed COVID-19 cases in Wuhan, China found that 14.8% of cases among healthcare workers were classified as severe or critical.4 In the United States, health care workers account for at least 6% of COVID-19–related hospitalizations, according to an analysis by the Centers for Disease Control and Prevention (CDC) of data collected early in the pandemic from 13 sites in 13 states.15

During the COVID-19 pandemic, aerosol-generating procedures increase the risk of infection among healthcare workers. To minimize the spread of COVID-19 within healthcare facilities and to reduce the risk of infection for healthcare workers, the following virus prevention recommendations have been issued:

  • N95 respirators or powered air-purifying respirators should be used when performing aerosol-generating procedures, in addition to other personal protective equipment (PPE) (i.e., gloves, gowns, face shield, or safety goggles).
  • Surgical masks are less effective in blocking aerosols and should not be used during aerosol-generating procedures. Surgical masks may be used when providing usual care for non-ventilated COVID-19 patients or when performing nonaerosol-generating procedures on mechanically ventilated COVID-19 patients.
  • Aerosol-generating procedures on COVID-19 patients should be performed in a negative-pressure room, or airborne infection isolation room (AIIR), when possible. Examples of aerosol-generating procedures include endotracheal intubation and extubation; bronchoscopy; open suctioning; high-flow nasal cannula (HFNC) or a face mask; nebulizer treatment; manual ventilation; physical proning of the patient; disconnecting a patient from a ventilator; mini-bronchoalveolar lavage; noninvasive positive pressure ventilation (NIPPV); tracheostomy; or cardiopulmonary resuscitation.16

Vaccine Clinical Trial Information – Since the beginning of the pandemic, vaccines against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been aggressively pursued.17 Standard vaccine platforms, as well as novel approaches (eg, mRNA vaccines), are being used to develop vaccine candidates. To shorten the lengthy process of vaccine development without compromising scientific rigor, vaccine candidates that show promise in phase 1 and 2 clinical trials are being rapidly moved into phase 3 trials.18

As of January 2021, two mRNA vaccines that encode the SARS-CoV-2 spike protein — BNT162b2 (Pfizer-BioNTech COVID-19 Vaccine) and mRNA-1273 (Moderna COVID-19 Vaccine) — have been granted Emergency Use Authorization (EUA) by the US Food and Drug Administration (FDA) for the prevention of COVID-19.19,20 BNT162b2 is indicated for individuals 16 years of age or older; mRNA-1273 is indicated for individuals 18 years of age or older. Both vaccines are given intramuscularly in 2 doses (21 days apart for BNT162b2 and 28 days for mRNA-1273).

Available phase 3 trial data indicate that both BNT162b2 and mRNA-1273 have largely similar efficacy and safety profiles.21, 22 Both vaccines show high efficacy (~95%) in preventing symptomatic COVID-19 infections. Recipients of both vaccines reported local (pain, swelling, etc) and systemic reactions (fatigue, headache, fever, chills, etc), which were more mostly mild to moderate and resolved rapidly. Reactions were reported more often by younger vaccine recipients than older recipients and more commonly after the second dose than the first dose. Rare cases of severe allergy (eg, anaphylaxis) and an anecdotal finding of a slight excess of Bell’s palsy incidence were also reported.

The CDC has issued and constantly updates its clinical guidance for healthcare professionals and pharmacists on COVID-19 vaccination, including information on contraindications and precautions, storage and handling, administration, management and reporting of adverse effects, and patient education for each specific vaccine.23

Passive Vaccination – Casirivimab and imdevimab are neutralizing monoclonal antibodies that target the receptor-binding domain of the spike protein of SARS-CoV-2 and prevent the virus from entering host cells.24 According to a press release from the manufacturer, interim results from a phase 3 trial (NCT04452318) suggest that casirivimab plus imdevimab may help prevent COVID-19 in people at high risk of infection (due to household exposure to COVID-19).25 In an exploratory analysis, no symptomatic COVID-19 infections occurred among participants who received casirivimab plus imdevimab (0/186 vs 8/223 among placebo recipients), indicating 100% prevention of symptomatic infection. Compared to placebo recipients, the incidence of overall COVID-19 infections (symptomatic and asymptomatic) was ~50% lower among treatment recipients (10/186 vs 23/223). Infections that occurred among treatment recipients were all asymptomatic, with decreased peak virus levels and short duration of viral shedding.

References

  1. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720.
  2. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507-513.
  3. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, March 1–30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:458-464.
  4. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323:1239-1242.
  5. Phua J, Weng L, Ling L, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med. 2020;8:506-517.
  6. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.
  7. Centers for Disease Control and Prevention (CDC) COVID-19 response team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:343-346.
  8. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;3:1-3.
  9. Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-19 infection. Clin Chem Lab Med. 2020;58(7):1131-1134.
  10. Bersanelli M. Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors. Immunotherapy. 2020;12:269-273.
  11. Chen L, Liu HG, Liu W, et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Chin J Tuberc Respir Dis.2020;43:E005 [Abstract in English].
  12. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061-1069.
  13. Calabrò L, Peters S, Soria JC, et al. Challenges in lung cancer therapy during the COVID-19 pandemic. Lancet Resp Med. 2020;8(6):542-544.
  14. Kooraki S, Hosseiny M, Myers L, Gholamrezanezhad A. Coronavirus (COVID-19) outbreak: what the department of radiology should know. J Am Coll Radiol. 2020;17:447-451.
  15. Kambhampati AK, O’Halloran AC, Whitaker M, et al; COVID-NET Surveillance Team. COVID-19-associated hospitalizations among health care personnel – COVID-NET, 13 states, March 1-May 31, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(43):1576-1583.
  16. National Institutes of Health (NIH). Infection Control. Available at https://covid19treatmentguidelines.nih.gov/critical-care/infection-control/.
  17. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 vaccines at pandemic speed. N Engl J Med. 2020;382(21):1969-1973.
  18. National Institutes of Health (NIH). Prevention and Prophylaxis of SARS-CoV-2 Infection. Available at https://www.covid19treatmentguidelines.nih.gov/overview/prevention-of-sars-cov-2/.
  19. US Food and Drug Administration (FDA). Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19). Fact Sheet for Healthcare Providers Administering Vaccine. Available at https://www.fda.gov/media/144413/download.
  20. US Food and Drug Administration (FDA). Emergency Use Authorization (EUA) of the Moderna COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19). Factsheet for Healthcare Providers Administering Vaccine. Available at https://www.fda.gov/media/144637/download?utm_medium=email&utm_source=govdelivery.
  21. Polack FP, Thomas SJ, Kitchin N, et al; C4591001 Clinical Trial Group. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603-2615.
  22. Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020;NEJMoa2035389. doi: 10.1056/NEJMoa2035389.
  23. Centers for Disease Control and Prevention (CDC). COVID-19 Vaccination. Available at https://www.cdc.gov/vaccines/covid-19/index.html.
  24. Weinreich DM, Sivapalasingam S, Norton T, et al; Trial Investigators. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med. 2021;384(3):238-251.
  25. Regeneron Pharmaceuticals. Regeneron Reports Positive Interim Data with REGEN-COV™ Antibody Cocktail used as Passive Vaccine to Prevent COVID-19. Available at https://investor.regeneron.com/news-releases/news-release-details/regeneron-reports-positive-interim-data-regen-covtm-antibody.
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Clinical Toolkit

The COVID-19 Clinical Toolkit is an online tool that aims to provide clinicians with up-to-date information on the presentation, prognosis, pathophysiology, and treatment strategies for COVID-19. Click on one of the options below to learn more.

This activity is provided by Med Learning Group. This activity is co-provided by Ultimate Medical Academy/CCM.
This activity is supported by educational grants from AbbVie, Astellas, Genentech, Lilly, Merck & Co., Inc., Pfizer and Regeneron Pharmaceuticals, Inc.

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Updates in the Treatment and Prevention of COVID-19​

Subcutaneous Administration of Casirivimab and Imdevimab Reduced the Risk of Symptomatic COVID-19 by 81% Among Household Contacts

Top-line results from a phase 3 trial showed that the combination of casirivimab and imdevimab reduced the risk of symptomatic infections by 81% among household contacts of SARS-CoV-2 infected individuals. The trial enrolled 1,505 individuals who did not have COVID-19 symptoms or anti-SARS-CoV-2 antibodies, but who lived in the same household as an individual who tested positive for SARS-CoV-2 within the prior 4 days. A single subcutaneous injection of casirivimab and imdevimab provided rapid protection to those with exposure to SARS-CoV-2 at home, with protection against symptomatic infections ranging from 72% in the first week to 93% in subsequent weeks. Individuals who developed symptomatic infections despite casirivimab and imdevimab therapy had a shorter duration of symptoms compared with those who received placebo (1 week vs 3 weeks, respectively). Infected individuals who received therapy also cleared the virus faster. Adverse events (AEs) occurred in 20% of patients receiving casirivimab and imdevimab and 29% of patients receiving placebo. Injection site reactions, all of which were grades 1-2, occurred in 4% of patients in the treatment group and 2% of placebo participants.

Casirivimab and Imdevimab Significantly Reduced Progression to Symptomatic COVID-19 in Recently Infected Asymptomatic Patients

In a phase 3 trial of 204 recently infected asymptomatic COVID-19 patients, subcutaneous administration of casirivimab and imdevimab reduced the overall risk of progressing to symptomatic COVID-19 by 31%, and by 76% after the third day. In addition to reducing the risk of symptomatic infections, the top-line results report that the combination of casirivimab and imdevimab shortened the total number of weeks patients experienced symptoms by 45% and reduced the viral burden by more than 90%. No patients withdrew from the trial due to AEs in either group. Casirivimab and imdevimab are investigational drugs with emergency use authorization for the treatment of individuals with mild-to-moderate COVID-19 who are at high-risk of progressing to severe COVID-19 or hospitalization. Casirivimab and imdevimab (REGEN-COV™) continues to be evaluated in clinical trials in multiple settings for COVID-19, including the open-label RECOVERY trial of hospitalized patients in the UK.

Johnson & Johnson COVID-19 Vaccine Administration Paused

The Centers for Disease Control and Prevention (CDC) and the Federal Drug Administration (FDA) are recommending a pause in the use of the Ad26.COV2.S vaccine developed by Johnson & Johnson (Janssen) as they review data involving 6 reported cases of a rare and severe type of blood clot in individuals after vaccination. The vaccine has been administered to more than 6.8 million individuals in the US. In all 6 reported cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) occurred in combination with low platelet levels (thrombocytopenia). Treatment of CVST differs from other blood clots and administration of heparin may be dangerous in these patients. All 6 cases occurred among women aged 18 to 48 years and symptoms usually occurred 6 to 13 days after vaccination. People who develop severe headache, abdominal pain, leg pain, or shortness of breath within 3 weeks after vaccination should contact their healthcare provider.

References:

Regeneron Press Release. Phase 3 Prevention Trial Showed 81% Reduced Risk of Symptomatic SARS-CoV-2 Infections with Subcutaneous Administration of REGEN-COV™ (Casirivimab and Imdevimab). April 12, 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-prevention-trial-showed-81-reduced-risk-symptomatic-sars

Regeneron Press Release. Phase 3 Treatment Trial in Recently Infected Asymptomatic Patients Showed REGEN-COV™ (Casirivimab and Imdevimab) Significantly Reduced Progression to Symptomatic COVID-19. April 12, 2021. Available at: https://investor.regeneron.com/news-releases/news-release-details/phase-3-treatment-trial-recently-infected-asymptomatic-patients

FDA Statement. Joint CDC and FDA Statement on Johnson & Johnson COVID-19 Vaccine. April 13, 2021. Available at: https://www.fda.gov/news-events/press-announcements/joint-cdc-and-fda-statement-johnson-johnson-covid-19-vaccine